Integrative Cell Signaling Faculty

Karen Anderson The research in our laboratory is directed toward understanding the molecular mechanisms of normal and aberrant protein signaling and the effects of selectively guided anticancer drugs such as Iressa and Gleevec. Important molecular targets include EGFR, HER-2, PDGFRb, and c-kit receptor tyrosine kinases (RTKs). We are particularly interested in examining the early events in cell signaling such as RTK autophosphorylation and downstream signal propagation. We are developing new molecular tools using electrospray ionization mass spectrometry and rapid cellular quench methodologies to aid in our investigations.

Anton Bennett The broad focus of our laboratory is towards understanding how signaling pathways that are regulated by protein phosphorylation are controlled and what the consequences are when these pathways become dysregulated in the pathogenesis of human disease. Specifically, we study a family of enzymes known as protein tyrosine phosphatases (PTPs). We use an integrative approach employing biochemistry, cell biology and mouse genetics to uncover the function of PTPs at the cellular level and in the intact organism. By using this integrated strategy we are able to understand how PTPs participate in intracellular signal transduction pathways that control cell growth, differentiation and metabolism.

Titus Boggon Rearrangement of the actin cytoskeleton is a critical for cellular structure, cell division,motility, intracellular transport, and a variety of other functions. Rho smallGTPase signaling cascades are key regulators of these rearrangements, and our goal is to answer the question:“What are the molecular mechanisms that control Rho signaling cascades?”To do this we use X-ray crystallography, cryo-electron microscopy, small-angle X-ray scattering, biochemistry, biophysics and cellular studies. Illustrative topics that we have addressed include:discovering how a Rho effector kinase is autoregulated, defining a unique kinase-substrate interaction that controls actin depolymerization, and discovering new pseudoGTPase domains in an important RhoGAP protein. We also probe the regulation mechanisms ofa Rho-associated signaling pathway which causes a severe neurovascular disorder. Overall, our lab hopes to significantly improve the molecular level understanding of these important pathways.

David Calderwood Our interests center on signaling through the integrin family of cell adhesion receptors. Integrin signaling regulates cell shape, adhesion and motility, furthermore cross-talk with other signal transduction cascades allows local environmental cues sensed by integrins to modulate a diverse array of signaling activities and control cell proliferation, differentiation, and death. Integrins are transmembrane adhesion molecules that connect extracellular ligands to intracellular signaling complexes and the cytoskeleton, and a notable feature is that intracellular signals that impinge on the integrin cytoplasmic domains also regulate integrin affinity for extracellular ligands. Integrins therefore signal in two directions across the membrane, into and out-of the cell. We use biochemical, cell biological and structural approaches to investigate the protein-protein interactions that govern integrin signaling and to assess the functional consequences of specific interactions.

Joseph Contessa Our laboratory studies mechanisms of therapeutic resistance to radiation therapy and we have identified EGFR signaling as a actionable target for improving cancer therapy.In combination with our HTS screening program, we are identifying new targets that alter tumor biology and sensitize cancer cells to treatment. Investigations of altered signaling involve both in vitro and in vivo models with the goal of translating our findings to clinical applications.

Craig Crews The Crews lab is interested in exploring various signaling transduction pathways using small molecules, including both biologically active natural products and artificially designed bioactive compounds. Of particular interest is the MAPK/MEK/Raf kinase cascade and the role of Wnt signaling in angiogenesis.

Kathryn Ferguson We are interested in extracellular control of receptor tyrosine kinases (RTKs) in both normal and neoplastic environments. For most(if notall)RTKs,regulation involves more than simple ligand-induced dimerization. RTKs are subject to complex allosteric regulation by their ligands, co-receptors and other modulators. We are particularly interested in the regulatory mechanisms of RTKs that appear to rely on higher order oligomerization or clustering for their biological activity, such as the Tie receptor family that plays key roles in angiogenesis. We have shown that the ligand-regulated member of this family, Tie2,is a constitutive dimer. Tie2 activation requires an oligomeric ligand and is modulated by co-receptors such as the orphan receptor Tie1. We seek to understand regulation of such ‘complex’ RTKs using a combination of biochemical, structural and cellular approaches.

Sourav Ghosh Our laboratory studies principles of signaling that ensure a physiological immune response by regulating its magnitude, specificity and duration. We also study cell polarity signaling in development and diseases.

Daryl Klein Our primary research interest is to decipher the control logic that regulates signaling relays important for the development of cancer and metastasis. Such regulatory principles are often hard-wired into the physical, thermodynamic and kinetic parameters of each system. We therefore approach our studies “bottom up” –building from an atomistic perspective. Our goal is to reveal, and ultimately harness the signaling logic to rewrite oncogenic programs in cancer. Our studies primarily target proteins found onthe surface of cancer cells. These include adhesion molecules, receptor kinases/phosphatases and immune checkpoint sensors.

Mark Lemmon A major focus of the Lemmon lab has been to understand transmembrane signaling by growth factor receptor tyrosine kinases (RTKs), of which there are 58 in the human proteome that fall into 20 different families. Mutations in almost all of these RTKs –someactivating, some inactivating –cause cancer or other diseases, making the RTKs important therapeutic targets. We are interested in understanding how these receptors signal, and –importantly –how RTK mutations seen in afflicted patients affect receptor activity. We combine cellular, biochemical, and structural approaches to understand molecular mechanisms of RTK signaling, doing our best to exploit this mechanistic understanding to advance development and application of receptor-targeted therapeutics. Collaborating closely with geneticists and clinical investigators, our goal is to link detailed mechanistic understanding to biology in the intact organism (or patient). In recent work, we discovered how alterations in the lifetime of the activated EGF receptor might underlie biased agonism by its different ligands. Another key focus is to determine how RTKs with intracellular pseudokinases function -particularly in Wnt signaling. Although much of our work has focused on RTKs and RTK signaling, we are also very interested in other poorly understood receptors –one recent new direction being mechanistic aspects of immunomodulatory co-receptors such as Tim3.

Elias Lolis The lab’s focus is understanding how agonist binding to a receptor induces a signal through the cell membrane. Specifically, we are interested in chemokines and their receptors as well as the cytokine macrophage migration inhibitor factor (MIF) and its effect on activating multiple receptors.

Kathleen Martin We are focused on understanding the phenomenon of “phenotypic switching” in the vascular smooth muscle cells that make up the blood vessel wall. Mature smooth muscle cells can de-differentiate ortrans-differentiate to a range of phenotypes(including myofibroblast, macrophage-like, and calcific), which can facilitate vascular growth and wound healing, but also contributes to cardiovascular pathologies including atherosclerosis, restenosis, aneurysm, and graft vasculopathy. Using in vitro and in vivo models,we aim to understand how signaling by growth factors (PDGF, TGFβ), cytokines (IFNγ), and therapeuticdrugs (rapamycin, prostacyclin) targetsepigenetic and transcriptional regulators to modulate smooth muscle phenotype.

Angus Nairn The focus of this lab is on the molecular actions of dopamine in the basal ganglia. The disruption of normal dopaminergic neurotransmission is known to underlie certain neurological diseases, including schizophrenia, Huntington's and Parkinson's disease, and is involved in the actions of various drugs of abuse.

Marina Picciotto Intracellular signaling pathways mediate changes in synaptic strength and neuronal function that underlie changes in behavior. Our laboratory is interested in the molecular basis of behavioral changes related to psychiatric illness. We therefore study intracellular signaling pathways downstream of nicotinic acetylcholine receptors and receptors for the neuropeptide galanin in order to determine how activation of these molecules leads to long-term changes in cellular-and circuit-level function in the brain, and ultimately to drug addiction, depression and aversive learning.

Carla Rothlin Inflammation involves a complex interplay of biochemical pathways that trigger and shape the immune response. These culminate in a coordinated response that is essential for protection against invading pathogens. Inflammation, if unchecked, can favor the development of chronic inflammatory and autoimmune diseases. Thus, mechanisms that regulate its duration and intensity are fundamental to immune homeostasis. Our research interest is to elucidate the mechanisms that underlie the regulation of inflammation and the homeostatic control of immune function. We have discovered a signaling pathway downstream of the TAM (Tyro3, Axl, Mer) receptor tyrosine kinases that limits the amplitude and phase of the inflammatory response. We are currently focusing on identifying the in vivo source of TAM ligands, unraveling the molecular determinants that account for the specificity of TAM-mediated inhibition, decoding the transcriptome activated during TAM-mediated inhibition of inflammation, and testing the role of TAM-mediated immune suppression in vivo. Our long-term goal is to manipulate this pathway as an innovative therapeutic strategy for the inhibition or enhancement of the inflammatory response.

Joseph Schlessinger Our laboratory is using a variety of genetic, biochemical and biophysical approaches to elucidate the intracellular signaling pathways that are activated by RTK. We also explore the role played by deregulated and aberrantly activated RTKs and their intracellular signaling pathways in the control of cancer and other human pathologies. Our goal is to decipher the intercellular molecular circuitry including both positive and negative signals that govern RTK dependent cellular processes such as cell proliferation, differentiation, cell survival and metabolism normally and in human pathologies.

William C. Sessa Our laboratory is interested in the role of microdomains in regulating the fidelity of signal transduction in vascular endothelial cells using a variety of cell biological, molecular and biochemical techniques and genetic models in vivo. We are interested in how growth factors and mechanical stress couples to activation of nitric oxide synthesis via phosphorylation and protein-protein interactions.We also are studying how vascular endothelial cells process lipids such as triglycerides and cholesterol and are defining novel pathways that regulate lipid uptake and metabolism. Finally, we have identified the primary mechanism of how mammalian cells generate lipids required for protein glycosylation reactions and are committed to elucidate the structural basis of this conserved enzyme system.

Ben Turk We are interested in understanding how protein kinases target specific protein substrates, thus ensuring proper transmission of intracellular signals. We take an interdisciplinary approach combining structural biology, combinatorial library screening, biochemistry, and cell biology to unravel the basic rules by which kinases are directed to their substrates in living cells. Understanding these rules allows us to identify new substrates for kinases through bioinformatics, and to probe the functional consequences of disrupting kinase-substrate interactions.

Dianqing (Dan) Wu We study the signaling mechanisms activated by chemoattractants and Wnts and how these signaling mechanisms function in physiological and pathophysiological processes including inflammation, tumor immunology, tumorigenesis, metabolic diseases.A combination of molecular and cell biological, biochemical, chemical biological, transgenic, functional genomics, and proteomic approaches are being used in our study.

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